Small molecules and a pharmacophore model for inhibition of...

Data processing: structural design – modeling – simulation – and em – Simulating nonelectrical device or system – Biological or biochemical

Reexamination Certificate

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Reexamination Certificate

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07574340

ABSTRACT:
Disclosed herein is a pharmacophore model for inhibiting Botulinum neurotoxin A metalloprotease activity which comprises a first plane A, a second plane B, a first hydrophobic moiety C, a second hydrophobic moiety D and a positive ionizable substituent E. The pharmacophore model may further comprise a heteroatom in the first plane A. In some embodiments, the distance between the center of the first plane A and the center of the second plane B is about 6.5 to about 9.5 Å. In some embodiments, the distance between the center of the first hydrophobic moiety C and the center of the second hydrophobic moiety D is about 8.0 to about 16.0 Å. In some embodiments, the distance between the center of the first plane to the center of the first hydrophobic moiety C is about 3.0 to about 5.0 Å. In some embodiments, the distance between the center of the second plane to the center of the second hydrophobic moiety C is about 3.0 to about 5.0 Å. In some embodiments, the distance between the center of the first plane to the center of the positive ionizable substituent is about 6.5 to about 9.5 Å.

REFERENCES:
patent: 6531126 (2003-03-01), Farmer
patent: 2005/0038246 (2005-02-01), Arnold et al.
Lacey et al. “Crystal Structure of Botulinum Neurotoxin Type A and Implications for Toxicity,” Nature Structural Biology (1998) vol. 5, No. 10, pp. 898-902.
Schmidt et al. “Type A Botulinum Neurotoxin Proteolytic Activity: Development of Competitive Inhibitors and Implications for Substrate Specificity at the S1' Binding Subsite,” FEBS Letters (1998) vol. 435, pp. 61-64.
Deshpande et al. “Efficacy of Certain Quinolines as Pharmacological Antagonists in Botulinum Neurotoxin Poisoning,” Toxicon (1997) vol. 35, No. 2, pp. 433-445.
Penzotti et al. “A Computational Ensemble Pharmacophore Model for Identifying Substrates of P-Glycoprotein,” Journal of Medicinal Chemistry (2002) vol. 45, No. 9, pp. 1737-1740.
Bajorath, Jurgen “Integration of Virtual and High-Throughput Screening,” Nature Reviews Drug Discovery (2002) vol. 1, pp. 882-894.
Vennerstrom, et al. (1998) “Bisquinolines. 2. Antimalarial N,N-Bis(7-chloroquinolin-4-yl)heteroalkanediamines” J. Med. Chem. 41:4360-4364.

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